SYNTHESIS : To a solution of 2.0 g
5-methoxyindole-3-carboxaldehyde in 25 g nitroethane there was added
0.5 g anhydrous ammonium acetate, and the mixture held at reflux for
1.5 h on the steam bath. The excess nitroethane was removed under
vacuum yielding a wet, orange solid. This was dissolved in 20 mL
boiling isopropanol which, after cooling, deposited bright orange
crystals. These were removed by filtration, washed with cold
isopropanol, and air dried to provide 1.56 g
1-(5-methoxyindol-3-yl)-2-nitropropene mp 179-180 °C (lit. 182-184
°C). Evaporation of the filtrates gave 0.81 g crude product which
was recrystallized from 10 mL ethanol giving a second crop as dull
gold crystals. This weighed, after EtOH washing and air drying, 0.57 g
(80%), mp 178-179 °C.
A solution of 1.54 g 1-(5-methoxyindol-3-yl)-2-nitropropene in 60 mL
anhydrous THF was added dropwise to 50 mL 1 M LAH in THF, well
stirred, in an argon atmosphere. Each drop generated a red color which
immediately discolored. The addition took 0.5 h and the reaction
mixture was held at reflux for 18 h, then allowed to stir at room
temperature for 7 days. There was added, in sequence, 1.6 mL H2O in 10
mL THF (much gas evolution), 1.6 mL 15% aqueous NaOH (no more gas) and
finally 5 mL H2O. The Al2O3 was removed by filtration, washed with
THF, and the combined filtrate and washing stripped of solvent under
vacuum. The residue (1.83 g of a clear oil) was dissolved in 300 mL
dilute HCl, washed with 3x50 mL CH2Cl2, made basic with 25% NaOH, and
extracted with 3x50 mL of CH2Cl2. The extracts were stripped of
solvent under vacuum, and the 1.13 g residue distilled at the
KugelRohr. A clear oil distilled at 145-155 °C at 0.2 mm/Hg as a
white oil that spontaneously crystallized, mp 95-96 °C. MS (in
m/z): C2H6N+ 44 (100%); methoxyindolemethylene+ at 161/160 (88%, 43%,
again, as with the secondary amines, this primary amine has the 161
greater than the 160, nonmethoxylated tryptamines, the 131 greater
than the 130); 146 (22%); parent ion 204 (4%). These solids (0.51 g)
were dissolved in 5 mL boiling isopropanol, neutralized with several
drops of concentrated HCl, and diluted with Et2O. The solution became
turbid and scratching produced a fine white crystalline product. After
20 min standing this was removed by filtration, washed with Et2O, and
air dried. There was obtained 0.44 g 3-(2-aminopropyl)-5-methoxyindole
(a,O-DMS) as white crystals, with a mp of 216-218 °C. A sample
prepared some 20 years earlier (brown as the salt, not distilled as
the base, mp 220-222) now melted at 215-217 °C. The residue from
the aqueous acid wash above, contained no additional a,O-DMS as
assayed by TLC (19:1; CH3CN / NH4OH). The infra-red spectra are
different for these two material, indicating polymorphism. The new
white crystals; IR (in cm-1): 805, 816, 872, 1023, 1055, 1102, 1169,
NH at 3300. The old brown crystals; IR (in cm-1): 809, 839, 1021,
1041, 1080, 1112, 1170, NH at 3250. The brown morph, upon
recrystallization from IPA / Et2O had an IR identical to the new white
material.
DOSAGE : 2.5 - 4.5 mg
DURATION : 12 - 18 hrs
QUALITATIVE COMMENTS : (with 2.0 mg, orally) "Initial anxiety
about getting nauseated or having diarrhea was almost immediately
dissolved after ingestion. It took a little while before I felt the
energy. By the way, before I took the medicine, I had read some lurid
details about other people's experiences, and was rather anxious about
it, because there was a lot of diarrhea and vomiting mentioned. But it
didn't happen. Matter of fact, I felt really good afterwards. The
dosage level seemed just right. I had a very enjoyable
day. Communication was easy and fun. Sleep was easy to reach and it
was great. Next morning, feel wonderful. Would I repeat? Yes. At
about the same level."
(with 2.3 mg, orally) "It has been an hour and a half, but now I am
really turning on. Physically, I have had some pretty thorough
diarrhea, but mentally I am still waiting for some sensory or
perceptual, or conceptual event to occur. At the sixth hour I think I
am clearing, and I don't know what it was all about. It was as if I
was in a state of preparedness like a plate of sterile agar waiting to
provide nutrition to whatever was to be introduced into it. But there
was no inoculation. I didn't contribute my share. A good argument for
threshold being a better measure of drug potency than a full dose. Had
a slight fragile headache the next AM -- gone by noon."
(with 2.5 mg, orally) "Came on fairly nicely, but at about 40 minutes,
began to feel slightly nauseous. This stuck with me for a couple of
hours. I could get out of it by concentrating, so it wasn't
debilitating. But then, as I began to come out of that, felt a nice
warm glow, and a nice centered feeling, and felt really good the rest
of the day. Evening was very tired, and had a difficult time going to
sleep because there was still a powerful push from the substance. In
fact, I think it's the most tenacious stuff I've taken, and I never
could detect much let-up during the afternoon. Then, I don't think I
got into good sleep until about 2 a.m. No problem after that. Good
sleep. Next morning, felt good. Still a bit languid. Today feels
good. Everything looks and feels fine, but I'm not a ball of
energy. At the moment, haven't fully integrated it all. No great
enthusiasm about taking it again."
(with 3.0 mg, orally) "Just over an hour into it, some mild vomiting
relieved my nausea and I began building into a wild ASC. With my eyes
closed the cloud are rolling and I have strange imagery. I am going
into a zombie place, my walk is a bit Frankensteinish, the piano keys
are unreal, the typewriter keys are unreal -- music and text that
comes out has little bearing on my intentions. The most fun was
writing with the power off; no inhibitions, no record. Tried a bit
with the power on, and this is an exact copy of what came out: what an
alien keyboard - what will it produce? anilan alina anein alein alean
ailean alain alein wow wowowowowow. The face on the lion's chair is
many things, cheeks become boxing gloves, mouth talks but no words are
evident, entertaining but not profound. Such mileage from just three
milligrams of C, H, N & O. Obviously it is my own energy pool that has
been tapped. Fourth hour, diarrhea again -- modest -- just
symbolic. All through the last two hours -- in addition to the
interpretive changes, there were wild visual distortions. Things
tended to flow -- not bothersome -- but I know I couldn't drive a car.
Here was a marvelous chemical gestalt. Reasoning from the
o-hydroxybenzyl alcohol Rx c CN- Æ benzyl cyanide, why not
dehydrate HOPhCH=CHCH2OH, then reduce 1,6 Æ p-OH allylbenzene and
1,8 Æ p-OH propenylbenzene -- then -- if reduction goes from
methoxy group, a compound such as normetanephrine would Æ
two-carbon MDA (b-OH reduced off at expense of guaiacol becoming a
methylenedioxy). Phoned friend. He was amused.
By the fifth hour, I was mending; the physical zombie is not there
anymore. I can ignore the crawling. At the ten hour point I am still
dilated, and teeth rubby, and hypoxic. Something is still
poisonous. Sleep not satisfactory. Restless, with strange mental
interpretations. The next day, I am clear and totally without
residues. This a,O-DMS is probably the most potent indolic psychedelic
yet uncovered, at least via the oral route. Any higher dose would
require a baby-sitter, and I must remember that there is a big toxic
component that is part of this trip."
(with 3.5 mg, orally) "I started with 2.5 milligrams followed in two
hours by 1 more. Never got above 1.75 plus. Not much insight. Pleasant
generally, but essentially non-productive. Slept easily at post-lunch
nap time. Had trouble sleeping near midnight. Had to take a
Restoril. Sleep okay, but like 2C-B, dreams slightly annoying and
repetitive."
(with 4.0 mg, orally) "Slight nausea with no problem at an hour, and
then developed to a plateau for about a ++ for the three to seven hour
slot. I slept but was still not baseline at the 16 hour point. A
wonderful drug for interacting with others and formulating ideas. It
bestows a remarkable ability to multi-task mental activities. No
hang-over the next day, in fact quite the reverse. Can't wait to try 5
milligrams."
(with 4.5 mg, orally) "I started with 3.0 milligrams and with the
complete absence of physical malaise I supplemented with 1.5 milligrams
at two hours. There were some shakes appearing, but there was a super
window-state that developed, not intellectual, not psychotic, but things
are crawling. At five hours fully +++ but some beginning to drop, but
drop very slowly. The mental memory was there still at nine hours and
the mental memory at twelve hours. There was teeth clench."
(with 0.8 mg. of the R-isomer) "I feel excellent, but I felt excellent
before the experiment. No drug effect."
(with 1.5 mg of the R-isomer, orally) "There is a faint light-head-light
body feel about two hours into it. And light diarrhea at the fourth
hour. Certainly nothing at 6 hours."
(with 3.0 mg of the R-isomer, orally) "I am aware at one hour, and to a
real plus one at three hours. Still real at four hours, vaguely
pleasant, and the diarrhea is right on schedule. Pretty much out of
whatever this was, by eight hours."
(with 0.8 mg of the S-isomer, orally) "There is an honest threshold, a
real tingle at one hour. This clearly is the active isomer. At 2 1/2
hours, this is pushed up to a plus one, , not just in the body but there
is something active in the head. At the third hour, everything seems
stable, there is complete diarrhea, the body knows that it has been
affected, but there is some mental still. Six hours dropping, eight
hours clear, but there are body memories."
(with 2.4 mg of the S-isomer, orally) "I took 1.5 milligrams initially,
and was aware in a half hour. No nausea, but diarrhea. Stuck at a mental
plus two at three hours, so I augmented this with another 0.9
milligrams. The supplement became apparent in another half hour, and I
was at a +++ in short order. Not too much in the way of eyes-open visual
effects, but there was a thorough intoxication that lasted for another
three hours. Attempted sleeping at fifteen hours failed -- I am far too
guarded to sleep. Finally OK, but I don't remember my dreams. Next
morning, the body still not completely baseline. Is this ever the active
isomer!"
EXTENSIONS AND COMMENTARY : From the point of view of the
neuropharmacologist, this has to be one of the most appealing and
seductive of compounds. Serotonin (5-HT) is the "in" neurotransmitter,
and the first receptor system that is looked at in any research lab
working with psychedelic drugs. An association with serotonin is a
strong justification for grant writing and funds solicitation from the
mother of most medical research funding, the branches of the National
Institutes of Health in Washington. Although this specific
neurotransmitter is a big item in the brain, if you feed it to a
person, or put it into him via the blood or tissue, it can't get
there. It has no way of moving this specific molecule from the outside
of the brain (the periphery) into the brain itself (the central
Kingdom).
Two obstacles effectively prohibit this availability. Serotonin has a
free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a
big polar water-loving pimple which denies it any passage across the
brain's defensive Maginot Line, the blood-brain barrier. And there is
the second problem. There is a exposed amino group, the amine of T of
5-HT, the tryptamine, which is immediately removed by the body's
monoamine oxidase enzyme. In short, it is blocked from entry into the
brain because it is both too polar and too metabolically fragile.
The structure of alpha-O is designed to overcome these two
restrictions. A methyl group on the oxygen (the O-methyl) removes the
polarity restriction. A methyl group next to the amine function (the
alpha-methyl) protects the molecule from enzymatic attack. With the
two obstacles removed, this compound apparently has easy access
directly to the brain. Hence, alpha,O-dimethylserotonin (a,O-DMS) goes
directly into the central nervous system and has proved to be one of
the most potent tryptamines yet described. And it is active following
oral administration, where it is exposed to all of the body's
protective machinery.
I have been sent one report from an anonymous source, that told me
that the compound did not have any increased potency when it was
smoked. His report was with 5 milligrams, and said: "Not too intense a
smell, but it has quite a bite. Slow onset, unlike DMT. After a few
minutes there was some dizziness, light giddiness, dysphoria,
stretching of the limbs, some gastrointestinal disturbances, a sense
of the body floating, and pupil dilation. Even with the eyes closed,
and concentration, there were only indistinct visual
hallucinations. With the eyes open, a strong intensification of
colors, and a harmonization of visual impressions just like everything
was 'velvet coated and has its own mystical movement.' Sleep was
restless and on the next day there were some remaining effects with
tiredness and mental exhaustion." If the oral and a parenteral route
indeed both produce the same effects and show the same potency, the
argument against metabolic catabolism may be valid. This would be an
interesting experiment to repeat.
An additional complication and opportunity is provided by the fact
that the placement of the methyl group on the alpha-position
introduces a chiral carbon. The R- and S-isomers have been compared
(see in the Qualitative Comments section) and the S-isomer is clearly
three or four times more potent that the R-isomer. These were assayed
completely blind, with the code having been broken only after the
completion of the study. The dramatic differences in potency let the
assignment of the more active isomer be made without hesitation. This
S-isomer is the d- or dextrorotary one, and has the absolute
configuration of the active member of the isomer pairs of amphetamine,
of methamphetamine and of MDMA. All the psychedelic amphetamine
derivatives (all that have been assayed, that is) have the R-isomer as
the more potent one.
Some half of the subjects I specifically queried as to their sleeping
patterns confirmed my own observation that the dreams were generally
negative. A few actually had memories of catastrophes or high
danger. This, coupled with the extremely high potency of this compound
and many options for structural variation, allows a treasure trove of
speculation. The 5-methoxy group is in every way the positional
analogue of the 4-substituent in the phenethylamine world. Would the
5-ethoxy, the 5-isopropoxy, the 5-something-else-oxy provide
psychedelic compounds? Would alpha-ethyl or higher provide
anti-depressants, as had been seen with Ariadne and related
phenethylamines? Would N-substitution (N-methyl, N-isopropyl,
N,N-dimethyl, N-methyl-N-isopropyl) lead to orally active things with
increased potency or increased drama? Would any of these changes
improve the ratio of mental effects over the body toxicity? Are the
occasional nightmares reported with sleep following alpha-O unique to
this compound, or might a specific dream-modifying agent be uncovered
with structural modifications?
I am aware of one of these modifications, specifically on that magical
5-methoxy-position. This is the sterically similar, but metabolically
totally dissimilar fluorine analogue, 5-fluoro-alpha-methyltryptamine,
or 5-F-a-MT. The fluorine atom is the darling of the manipulators of
molecular structure in that it is a form of fake hydrogen. True, as an
atomic lump on an aromatic ring it is a lot larger and a lot heavier,
but it is a lump that doesn't like to associate with anything
else. It's bonding with a ring carbon is the same sort of two-electron
bond that the hydrogen atom makes, but it cannot be oxidized off in
the same way. So, when a drug has a position of sensitivity to
oxidation, and that oxidation is thought to be responsible for some
particular pharmacological property, put a fluorine there and you will
deny the drug that property. This was discussed in the section on DET
where the metabolism attacks a 6-position hydrogen.
And it may play such a role here. When one balances the sort-of
stimulant nature of a-MT with the potent psychedelic properties of
a,O-DMS, one can ask if the oxidation of the tryptamine system at this
5-position can be of some significance. Tryptamine becomes serotonin
by this action. DMT becomes bufotenine by this action. If there is
some extension of this to the a-MT world, then the placement of a
fluoro group at that position of attack would be interesting. 5-F-a-MT
has been made, and it appears to be of reduced activity in man. But it
has proven to be an extremely potent monoamineoxidase inhibitor, and
strongly influences the brain serotonin levels. The 6-fluoro isomer,
6-F-a-MT, is also effective.
This kind of molecular manipulation is the ultimate treasure of the
research pharmacologist. The taking off of one atom and the
replacement of it with another. This is the simplest single maneuver
that can be done to a drug, and any change in the observed
pharmacology must be the result of that change. Some of the
explorations have been described in this book are of exactly this
nature. Some have been tried. Most have not and are completely
unknown. All must eventually be explored if we ever hope to learn what
is going on up there in the human mind.
